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Method for producing sevoflurane

a technology of sevoflurane and sevoflurane, which is applied in the field of methods, can solve the problems of difficult separation of product and difficult separation of compound a from sevoflurane, and achieve the effects of effective use, effective use and convenient separation from sevofluran

Active Publication Date: 2018-09-04
CENT GLASS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This approach significantly reduces the amount of compound A in sevoflurane, allowing for the recovery of high-purity sevoflurane with improved yield and simplified operations by converting compound A into a separable species and utilizing residues for additional purification steps.

Problems solved by technology

Of these, a by-product that is difficult to separate is bis(fluoromethyl)ether.
For such reason, once the compound A is generated during purification of sevoflurane, it often becomes difficult to separate the compound A from sevoflurane (purification of sevoflurane).

Method used

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  • Method for producing sevoflurane
  • Method for producing sevoflurane

Examples

Experimental program
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Effect test

example 1

(Step 1)

[0153]A compound A (purity: 99% or more) (5 g), HF (20 g), water (100 g), and 1,2-dichloroethane (DCE) serving as an internal standard substance (15 g) were mixed, followed by stirring in an air-tight polytetrafluoroethylene resin container for 5 hours at 20° C. to 25° C., thereby conducting a reaction. During the reaction, the peak area ratio of [compound A] / [DCE] was determined by FID gas chromatograph analysis at 1-hour intervals. Note that a sample liquid was brought into contact with NaF for dehydrofluorination and then analyzed by gas chromatography (the retention time for the compound A was around 5.2 minutes and the retention time for DCE was around 16.5 minutes under the gas chromatography conditions).

[0154]As a result, although the peak area ratio of [compound A] / [DCE] was 0.57 immediately before the start of the reaction, it became 0.48, 0.38, 0.31, 0.25, and 0.19 in 1, 2, 3, 4, and 5 hours, respectively, after the start of the reaction. In other words, after the ...

example 2

(Step A)

[0156]The standard substance of the compound A (used in Example 1) was used so that “sevoflurane containing compound A at 100 ppm” was prepared. The obtained sevoflurane (1000 g) was introduced into a glass distillation tank. In addition, a 1% sodium hydrogen phosphate aqueous solution (70 g) was added thereto, followed by ordinary pressure distillation using a distillation column with 10 theoretical stages at a reflux ratio of 5 to 20.

[0157]The distillate was analyzed by FID gas chromatography and collected as a “first distillation fraction” while the compound A was detectable at 1 ppm or more. Then, when the compound A was detected at a level of less than 1 ppm, the distillate was collected as a “main distillation fraction.”

[0158]As a result, the recovered amount of the “first distillation fraction” was 267 g, in which the content of compound A was 341 ppm. Meanwhile, the recovered amount of the “main distillation fraction” was 720 g, in which no compound A was detected (l...

example 3

(Step 1b)

[0170]In Example 3 and the subsequent examples, a reaction corresponding to step 1b was conducted at a small scale (one-tenth scale of Example 2) as a model experiment similar to step 1a of Example 2 (using a small sealable stainless-steel reactor).

[0171]At first, the standard substance of compound A and sevoflurane were mixed so that “sevoflurane containing compound A at 340 ppm” was prepared. The sevoflurane was designated as a reaction material in Example 3 and the subsequent examples.

[0172]An “HF aqueous solution (prepared by dissolving 1.0 g of anhydrous HF in 5.0 g of water)” was added to 24 g of the “sevoflurane containing compound A at 340 ppm.” Further, 1.0 g of HFIP was added and an autoclave was closed. Stirring was initiated using a magnetic stirrer and the interior temperature was maintained at 20° C. to 25° C.

[0173]After the elapse of 5 hours, FID gas chromatography was conducted for determination. The conversion rate of compound A was estimated as 73%. As HFI...

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Abstract

An object of the present invention is to remove a compound A from “sevoflurane containing fluoromethyl-1,1,3,3,3-pentafluoroisopropenyl ether (compound A)” so as to collect high-purity sevoflurane. The present invention concerns a method for producing sevoflurane containing substantially no compound A, comprising the following steps of: bringing a composition containing hydrogen fluoride (HF) and water at a mass ratio of 1:1 to 1:30 into contact with a 1st organic liquid containing sevoflurane and a compound A, thereby obtaining a 2nd organic liquid containing the compound A in an amount that is lower than that in the 1st organic liquid (step 1a); and distilling the 2nd organic liquid under the presence of a degradation inhibitor, thereby obtaining sevoflurane containing substantially no compound A as a main distillation fraction (step 2).

Description

TECHNICAL FIELD[0001]The present invention relates to a method for producing fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether (sevoflurane) which has been widely used as medicines and especially inhalation anesthetics.BACKGROUND ART[0002]Fluoromethyl-1,1,1,3,3,3-hexafluoroisopropyl ether (sevoflurane) has been widely used as a safe inhalation anesthetic for use. As described in U.S. Pat. No. 4,250,334 (Patent Literature 1), sevoflurane can be synthesized by adding concentrated sulfuric acid and hydrogen fluoride to paraformaldehyde, heating the obtained reaction mixture, and adding 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIP) dropwise to the mixture. A substance of interest (i.e., sevoflurane) can be collected together with an unreacted substance (e.g., HFIP) by collecting a gas generated in the reaction system.[0003]Various by-products are generated in the above sevoflurane synthesis reaction. Of these, a by-product that is difficult to separate is bis(fluoromethyl)ether. Howev...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07C43/00C07C41/42C07C41/22
CPCC07C41/22C07C41/42C07C41/44C07C43/123C07C41/01
Inventor YOSHIMURA, TAKAAKIOONO, TOSHIHIKOAKIBA, SHINYAFUJIWARA, MASAKI
Owner CENT GLASS CO LTD
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